The discussion that follows is provided as background information to aid the reader in understanding the present invention and is not intended, nor is it to be construed, as being prior art to the invention.
A gel is a three-dimensional polymeric network that has absorbed a liquid to form a stable, usually soft and pliable, composition having a non-zero shear modulus. The liquid contributes a substantial percent of the overall volume of the composition. When the liquid is water, the gel is called a hydrogel. Due to their unique composition, i.e., largely water absorbed into a biologically inert polymeric matrix, hydrogels have found use in numerous biomedical applications.
For example, hydrogels are the virtual foundation of the soft contact lens industry. They are also used as wound dressings, both with and without incorporated medicaments that can be released from the matrix to aid in the healing process (U.S. Pat. Nos. 3,963,685 and 4,272,518). Hydrogels have been used as artificial sphincters for treatment of urinary incontinence by virtue of their ability to swell upon absorption of water (Sefc, et al., Biomaterials, 2002, 23:3711). They have also been used a coatings to enhance the wettability of medical devices such as blood filters (U.S. Pat. No. 5,582,794). In addition, hydrogels have found substantial use as vehicles for the sustained release of biologically active substances.
Thus, European Pat. App. No. 0246653 describes a drug delivery device that includes a partially hydrated, non-biodegradable hydrogel as a release-rate-limiting barrier. U.S. Pat. No. 5,292,515 discloses a method of preparing a hydrophilic reservoir drug delivery device using a variety of hydrogel compositions. Davidson, et al. report the use of hydrogel membranes for the controlled delivery of luteinizing horomone-releasing hormone (Proceed. Inter. Symp. Cont. Rel. Bioact. Materials, 1988, 15).
In all the above instances, the hydrogel used is in bulk polymeric form, that is, an amorphous mass of material with no discernable regular internal structure. The amorphous nature of the hydrogel may affect the homogeneity of a composite of the gel with other substances. Furthermore, bulk hydrogels usually have slow swelling rates due to the large internal volume compared to the surface area through which water can be absorbed. Their size makes them relatively poor vehicles for controlled release of bioactive substances. That is, a substance dissolved or suspended in the absorbed water will diffuse out of the hydrogel at markedly different rates depending on where it is in the matrix. A substance at or near the surface of the hydrogel will easily escape the gel matrix but material deeper within the matrix will have to diffuse a much longer distance before reaching the outer surface of the gel and being released. This situation can be ameliorated to some extent by the use of particulate hydrogels. If the particles are sufficiently small, substances dispersed in them will diffuse to the surface and be released at essentially the same rate.
Particulate hydrogels can be formed ab initio, for example, without limitation, by direct or inverse emulsion polymerization (Landfester, et al., Macromolecules, 2000, 33:2370) or they can be created from bulk hydrogels by drying the hydrogel, grinding the resulting xerogel and sieving the ground material to obtain particles of a desired size. The particles can then be re-hydrated to form particulate hydrogels. Using either of these approaches, particles having micro (10−6 meters (m)) to nano (10−9 m) range diameters can be produced. As noted above, with their small volumes, any given molecule of a bioactive substance entrapped within a particle has almost the same distance to travel to reach the outer surface of the particle as any other molecule, giving rise to the possibility of zero order, or very nearly so, release kinetics. Using particulate hydrogels, however, also has its problems. Among these are controlling the dissemination of the particles to, and localization of them at, a particular target site. In addition, as mentioned previously, bulk hydrogels can be shape-retentive rendering them useful in such applications as artificial sphincters, tissue delivery vehicles, tissue replacement (artificial cartilage) materials, etc., while currently available particulate hydrogel aggregates, cannot.
What is needed is a material that has the desirable characteristics of bulk hydrogels, shape-retention and, in certain applications, elastomericity, and of particulate hydrogel aggregates, individually small volumes that offer more controllable substance delivery rates. The present invention provides such a material—a shape-retentive, aggregate of hydrogel particles. It also provides uses for the aggregates including, but not limited to, the controlled delivery of bioactive substances.